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PubMed1982

A comparison of polyamine metabolism in normal and transformed baby-hamster-kidney cells.

Transformed baby-hamster-kidney cells contain higher intracellular concentrations of polyamines than do normal cells. The difference is greater in high-density confluent cultures. Transformed cells incorporate exogenous putrescine into the cells at a faster rate than do normal cells. They also show a marked increase in the rate of spermine biosynthesis compared with normal cells. Transformed cells grown to high cell densities released about 10% of their polyamines into the culture medium in a non-specific manner. In contrast, normal cells, under the same culture conditions, release up to 50% of their intracellular polyamines into the medium almost exclusively as free or conjugated spermidine. The elevated levels of polyamines found in transformed cells therefore appear to be the result of altered transport of polyamines across the cell membrane and of increased rates of biosynthesis.

Animals↗
PubMed1983

Differential effects of polyamines on the phosphorylation of chromatin-associated proteins.

Studies are presented on the nature of chromatin-associated phosphoproteins whose phosphorylation is influenced by polyamines. After labelling with 32P, chromatin-associated proteins were separated into four fractions. Fraction I comprised neutral and basic non-histone phosphoproteins, including high-mobility-group non-histones; fraction II consisted mostly of histones; fraction III consisted of a class of (salt-soluble) acidic non-histone phosphoproteins; and fraction IV consisted of residual (salt-insoluble) acidic non-histone phosphoproteins. The average relative distribution of protein in the four fractions (I-IV) was about 1:4:2:1 for both liver and prostate. However, tissue-dependent differences were observed in the incorporation of 32P in various protein fractions. In the presence of polyamines (e.g. 1 mM-spermine or 2 mM-spermidine) maximal stimulation of phosphorylation was observed in non-histone proteins of fraction I (160-180%), followed by that in non-histone proteins of fraction III (80-110%). The phosphorylation of residual non-histone proteins in fraction IV, and the small extent of phosphorylation of histones in fraction II, remained unaltered in the presence of polyamines. Thus polyamines do not stimulate the phosphorylation of all non-histone proteins; their stimulative effect is most prominent in the phosphorylation of neutral and basic non-histone proteins and a class of salt-soluble acidic non-histone proteins. In accord with our hypothesis, these differential effects of polyamines on phosphorylation of endogenous non-histone proteins may relate to the conformation of these substrates rather than to endogenous kinases.

Animals↗
PubMed1983

Polyamines inhibit phospholipid-sensitive and calmodulin-sensitive Ca2+-dependent protein kinases.

Effects of polyamines on various protein kinases were investigated. It was found that both phospholipid-sensitive Ca2+-dependent protein kinase and myosin light-chain kinase (a calmodulin-sensitive species of Ca2+-dependent protein kinase) were inhibited to different degrees by polyamines, with an approximate order of inhibitory potency of spermine = 1, 12-diaminododecane greater than spermidine = 1, 10-diaminodecane much greater than cadaverine = putrescine. Kinetic analysis revealed that spermine inhibited the phospholipid-sensitive enzyme non-competitively with respect to Ca2+ (Ki = 0.84 mM) and phosphatidylserine (Ki = 0.90 mM); it also inhibited myosin light-chain kinase non-competitively with respect to Ca2+ (Ki = 1.82 mM) and calmodulin (Ki = 2.73 mM). 1, 12-Diaminododecane, in comparison, inhibited the phospholipid-sensitive enzyme competitively with respect to Ca2+ (Ki = 0.45 mM) and phosphatidylserine (Ki = 0.50 mM); it also inhibited myosin light-chain kinase competitively with respect to calmodulin (Ki = 0.63 mM) but non-competitively with respect to Ca2+ (Ki = 1.49 mM). Moreover, spermine (0.5 mM) was found to inhibit markedly phosphatidylserine/Ca2+- and calmodulin/Ca2+-stimulated phosphorylation of endogenous proteins in rat brain particulate fraction. All the polyamines tested were practically without effect on cyclic AMP-dependent and cyclic GMP-dependent protein kinases. Polyarginine, like spermine, was found to be a more selective inhibitor of Ca2+-dependent protein kinases, whereas polyglutamate preferentially inhibited the cyclic nucleotide-dependent enzymes. The present results indicated that, in addition to certain lipophilic compounds (such as trifluoperazine, palmitoylcarnitine, adriamycin and naphthalenesulphonamide) and polypeptides with hydrophobic regions (such as melittin and polymyxin B) previously reported, polycationic compounds (exemplified by polyamines) could also inhibit the two classes of Ca2+-dependent protein kinases requiring either phospholipid or calmodulin as a cofactor. Because of the high cellular concentration (up to 10 mM) and the differential effects of polyamines, it is suggested that spermine, and to smaller extents spermidine and putrescine, may be involved in the regulation of certain Ca2+-dependent protein-phosphorylation systems in vivo.

Animals↗
PubMed1985

Induction of spermidine/spermine N1-acetyltransferase in rat tissues by polyamines.

Treatment of rats with spermidine, spermine or sym-norspermidine led to a substantial induction of spermidine/spermine N1-acetyltransferase activity in liver, kidney and lung. The increase in this enzyme, which was determined independently of other acetylases by using a specific antiserum, accounted for all of the increased acetylase activity in extracts from rats treated with these polyamines. Spermine was the most active inducer, and the greatest effect was seen in liver. Liver spermidine/spermine N1-acetyltransferase activity was increased about 300-fold within 6 h of treatment with 0.3 mmol/kg doses of spermine; activity in kidney increased 30-fold and activity in the lung 15-fold under these conditions. The increased spermidine/spermine N1-acetyltransferase activity led to a large increase in the liver putrescine content and a decline in spermidine. These changes are due to the oxidation by polyamine oxidase of the N1-acetylspermidine formed by the acetyltransferase. Our results indicated that spermidine was the preferred substrate in vivo of the acetylase/oxidase pathway for the conversion of the higher polyamines into putrescine. The induction of the spermidine/spermine N1-acetyltransferase by polyamines may provide a mechanism by which excess polyamines can be removed.

Acetyltransferases↗
PubMed1989

Cellular characterization of a new irreversible inhibitor of S-adenosylmethionine decarboxylase and its use in determining the relative abilities of individual polyamines to sustain growth and viability of L1210 cells.

S-(5'-Deoxy-5'-adenosyl)methylthioethylhydroxylamine (AMA) is an irreversible inhibitor of S-adenosylmethionine (AdoMet) decarboxylase, which is designed to bind covalently the pyruvate residue at the enzyme active site. In the present study the cellular effects of AMA were characterized for the first time in cultured L1210 leukaemia cells. At the approximate IC50 (concn. giving 50% inhibition; 100 microM), AMA decreased spermidine and spermine by more than 80% at 48 h while increasing putrescine more than 10-fold. As an indication of enzyme specificity, growth inhibition was fully prevented with exogenous spermidine. When compared with the irreversible inhibitor of ornithine decarboxylase, alpha-difluoromethylornithine (DFMO), at similar growth-inhibitory concentrations, AMA was less cytotoxic, as determined by colony-formation efficiency. In combination with AMA, DFMO eliminated the rise in putrescine and decreased growth in an additive manner. The near-total depletion of intracellular polyamine pools achieved with the drug combination provided an opportunity to examine the relative abilities of individual polyamines to support growth and viability. Of the three exogenously supplied polyamines, only spermidine fully sustained cell growth and viability at control values during incubations totalling 120 h. By contrast, spermine supported growth at 23% of control and viability at 8%. Putrescine was similarly ineffective, supporting growth at 13% of control and viability at 7%. The data indicate that, in L1210 cells, spermidine is apparently the preferred polyamine in growth-related functions and is capable of fully supporting cell growth by itself. However, because spermine and putrescine can also support growth to some extent, maximum interference with growth and viability is best achieved by strategies which deplete all three polyamine pools.

Adenosylmethionine Decarboxylase↗
PubMed1990

Specific regulation by endogenous polyamines of translational initiation of S-adenosylmethionine decarboxylase mRNA in Swiss 3T3 fibroblasts.

S-Adenosylmethionine decarboxylase (AdoMetDC) activity was elevated 18.8-fold in Swiss 3T3 fibroblasts which were depleted of cellular polyamines by using the inhibitor difluoromethylornithine (DFMO). Although the cellular level of AdoMetDC mRNA and the half-life of active AdoMetDC protein were also increased (4.3- and 1.5-fold respectively), together they could not account for the magnitude of the increase in AdoMetDC activity. These data suggested that the translation of AdoMetDC mRNA must be increased in the polyamine-depleted cells to account fully for the elevation in activity. The cellular distribution of AdoMetDC mRNA was examined in the polyamine-depleted cells, and it was found almost exclusively associated with large polysomes. In contrast, AdoMetDC mRNA in untreated controls was very heterogeneous, with the proportion associated with monosomes equal to that associated with large polysomes. The shift of the AdoMetDC message into large polysomes occurred within 18 h after addition of DFMO to the cultures and could be reversed by adding exogenous putrescine. The effect of polyamine depletion on AdoMetDC translation was specific, since there was no change in the distribution in polysomes of either actin mRNA or the translationally controlled mRNA encoding ribosomal protein S16 in the DFMO-inhibited cells. Thus the translational efficiency of AdoMetDC mRNA in vivo is regulated either directly or indirectly by the concentration of intracellular polyamines through a mechanism involving translational initiation, which results in a change in the number of ribosomes associated with this mRNA.

Adenosylmethionine Decarboxylase↗
PubMed1991

Role of polyamines in the transport in vitro of the precursor of ornithine transcarbamylase.

Polyamines induce the transport in vitro of the rat liver precursor of ornithine transcarbamylase (pOTC) into isolated rat liver mitochondria. The accumulation of this precursor at the level of binding to the mitochondrial surface has allowed us to establish that polyamines are involved in the interaction of the precursor with the mitochondrial surface. Transport of a chimeric protein having the signal sequence of pOTC fused to a fragment of the cytosolic protein human arginosuccinate lyase was also induced by polyamines. The sensitivity of the pOTC synthesized in vitro and of the chimeric protein to proteinases decreases in the presence of polyamines. This result suggests that polyamines may play a role in modulating the folding of precursors to favour their binding to mitochondria.

Animals↗
PubMed1992

Natural polyamines stimulate G-proteins.

The natural polyamines spermine and spermidine, the biosynthetic precursor putrescine and their analogues cadaverine and tyramine stimulate the GTPase activity of purified GTP-binding proteins (Go/Gi) from calf brain reconstituted into phospholipid vesicles. The order of potency was spermine greater than spermidine greater than putrescine = cadaverine greater than tyramine. The physiological relevance of this observation was assessed, showing the same order of potency of polyamines in the stimulation of peritoneal and tracheal rat mast cells. The activation of rat mast cells by polyamines was inhibited by benzalkonium chloride or by a 2 h pretreatment of the cells with pertussis toxin. The increase in inositol phosphates evoked by polyamines was also inhibited by pertussis toxin. Therefore we propose that intracellular polyamines might control the basal level of second messengers and modulate extracellular signals transduced through G-protein-coupled receptors.

Animals↗
PubMed1992

Uptake of polyamines by human endothelial cells. Characterization and lack of effect of agonists of endothelial function.

Uptake of polyamines by confluent monolayers of human umbilical-vein endothelial cells (HUVECs) was found to be time-, temperature- and concentration-dependent, energy-requiring, and saturable. Kinetic constants were putrescine Kt 3 +/- 1 microM, Vmax. 15 +/- 7 pmol/h per microgram of protein; spermidine, 0.7 +/- 0.2, 12 +/- 3; spermine, 1 +/- 0.7, 11 +/- 4. Putrescine uptake was inhibited by spermine or spermidine, whereas uptake of spermine or spermidine was not inhibited by 20 microM-putrescine. These data suggest the existence of two carriers, one shared by spermine and spermidine, and one capable of transporting all three polyamines. Pretreatment of HUVECs with thrombin (less than or equal to 10 units/ml; 1 h), bradykinin (less than or equal to 10 microM; 1 h), interleukin-1 (less than or equal to 100 units/ml; 2 h) or phorbol 12-myristate 13-acetate (less than or equal to 1.0 microM; 1 h), all known agonists of endothelial function, had no significant effect on polyamine uptake. These responses may be of importance in angiogenesis and wound healing, and could have pharmacological significance, for there is a growing interest in the use of polyamines or polyamine analogues as therapeutic agents.

2,4-Dinitrophenol↗
PubMed1993

Inhibition of calcium signalling in murine splenocytes by polyamines: differential effects on CD4 and CD8 T-cells.

Transmembrane Ca2+ influx is recognized as a universal second messenger that transduces T-cell activation signals to cytoplasm and nucleus, thereby stimulating transcription and cell division. To examine the role of endogenous factors that regulate mitogenic Ca2+ signalling of T-cells, we measured the concanavalin (Con) A-induced increase in cytoplasmic free calcium ([Ca2+]i) in spleen cells of BALB/c mice, using flow cytometry with an indicator dye, Indo-1 acetoxymethyl ester (Indo-1/AM). Con A is a polyclonal activator of T-cells. Unstimulated splenocytes had a [Ca2+]i of 100 nM. [Ca2+]i increased with Con A in a dose-dependent manner up to a concentration of 50 micrograms/ml. In the presence of 50 micrograms/ml Con A, [Ca2+]i was 350 nM. Natural polyamines (putrescine, spermidine and spermine) inhibited Con-A-induced Ca2+ influx in a dose-dependent manner. Putrescine was the most effective polyamine in desensitizing the Ca2+ signal, and decreased [Ca2+]i from 350 nM in the absence of putrescine to 250 nM in the presence of 100 microM putrescine. This effect was not mimicked by structurally related homologues or inorganic cations, suggesting a specific structural effect of the polyamine. H.p.l.c. analysis showed that polyamines were internalized during incubation of cells in vitro. In experiments using monoclonal anti-CD4 and anti-CD8 antibodies, we found a differential effect of putrescine on Ca2+ influx in CD4 and CD8 subpopulations of T cells. For CD4+ cells, [Ca2+]i decreased from 625 nM to 420 nM in the presence of 500 microM putrescine, whereas [Ca2+]i was not affected by putrescine in CD8+ cells. These data suggest that natural polyamines have cell-specific effects on mitogen-stimulated Ca(2+)-influx in T-cell subsets.

Animals↗
PubMed1994

Polyamine-induced Z-DNA conformation in plasmids containing (dA-dC)n.(dG-dT)n inserts and increased binding of lupus autoantibodies to the Z-DNA form of plasmids.

Blocks of potential Z-DNA-forming (dA-dC)n.(dG-dT)n sequences are ubiquitous in eukaryotic genomes. We examined whether naturally occurring polyamines, putrescine, spermidine and spermine, could provoke the Z-DNA conformation in plasmids pDHf2 and pDHf14 with 23 and 60 bp inserts respectively of (dA-dC)n.(dG-dT)n sequences using an e.l.i.s.a. Spermidine and spermine could provoke Z-DNA conformation in these plasmids, but putrescine was ineffective. For pDHf2 and pDHf14, the concentration of spermidine at the midpoint of B-DNA to Z-DNA transition was 25 microM, whereas that of spermine was 16 microM. Polyamine structural specificity was evident in the ability of spermidine homologues to induce Z-DNA. Inorganic cations, Co(NH3)6(3+) and Ru(NH3)6(3+), were ineffective. Our experiments also showed increased binding of anti-DNA autoantibodies from lupus patients as well as autoimmune MRL-lpr/lpr mice to pDHf2 and pDHf14 in the presence of polyamines. These data demonstrate that small blocks of (dA-dC)n.(dG-dT)n sequences could assume the Z-DNA conformation in the presence of natural polyamines. Increased concentrations of polyamines in the sera of lupus patients might facilitate immune complex-formation involving circulating DNA and anti-Z-DNA antibodies.

Animals↗
PubMed1994

Inhibition of immediate-early-gene induction in renal mesangial cells by depletion of intracellular polyamines.

Mitogens have been shown to stimulate the activity of the rate-limiting enzyme for polyamine synthesis, ornithine decarboxylase (ODC), and ODC mRNA expression in cultured rat mesangial cells (MCs). In addition, inhibition of ODC by alpha-difluoromethylornithine (DFMO) results in growth arrest of MCs. To elucidate the mechanisms involved in the inhibition of MC proliferation due to polyamine depletion, we studied the effects of DFMO on the activation of phospholipase C and induction of the immediate early genes (IEGs), c-fos, c-jun and Egr-1, which are thought to regulate cell growth. Mitogenic 10% fetal-calf serum (FCS) and 1 unit/ml thrombin activated phospholipase C in MCs within 30 s, as assessed by generation of [3H]inositol phosphates. This activation was not affected by DFMO. mRNAs of the IEGs c-fos, c-jun and Egr-1 were induced by FCS within 15 min. Expression of these genes reached a peak at 60 min and disappeared at 3 h. Treatment of MCs with a growth-suppressing dose of DFMO (5 mM) inhibited mRNAs of all three IEGs by 52-87% at 1 h. Total expression of Egr-1 over 20-120 min was diminished by 41%, and the time point of maximal expression was delayed by 40 min. This inhibitory effect was abolished in a time-dependent manner (1-3 days) by prior addition of 200 microM putrescine, the reaction product of ODC. Egr-1 mRNA expression was super-induced by the inhibitor of protein synthesis, cycloheximide. This effect was also blocked by DFMO. The results indicate that the DFMO-induced process of MC growth inhibition involves steps necessary for IEG activation. The signal-transduction step sensitive to polyamines occurs distal to the activation of phospholipase C. Since reconstitution of normal induction of IEGs requires 3 days, it seems likely that polyamine depletion affects the regulation of IEG expression in an indirect fashion. We conclude that activation of IEGs requires the presence of polyamines and plays a significant role in the induction of MC replication.

Animals↗
PubMed1994

Forced expression of antizyme abolishes ornithine decarboxylase activity, suppresses cellular levels of polyamines and inhibits cell growth.

Ornithine decarboxylase (ODC) is a key enzyme in polyamine biosynthesis. It is a short-lived protein and negatively regulated by its products, polyamines. Its degradation is accelerated by the binding of antizyme, an ODC-inhibitory protein induced by polyamines. To evaluate the physiological importance of antizyme we examined the effect of forced expression of antizyme on cellular ODC and polyamine levels and cell growth. Antizyme almost completely abolished the induction of ODC by growth stimuli. This may have been caused by antizyme-induced rapid degradation of newly synthesized ODC, since the half-life of ODC complexes with antizyme was less than 5 min. Forced expression of antizyme caused reductions of cellular putrescine and spermidine levels, and inhibited cell growth, which was partially restored by the addition of putrescine. These observations suggested a critically important role of antizyme in polyamine metabolism.

Animals↗
PubMed1995

Defective signal-transduction pathways in T-cells from autoimmune MRL-lpr/lpr mice are associated with increased polyamine concentrations.

We previously reported that difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, exerted significant beneficial effects on the lifespan and disease expression of MRL-lpr/lpr mice, which spontaneously develop a lupus-like syndrome. Polyamine levels in splenic T-cells of MRL-lpr/lpr mice were significantly higher than those of Balb/c mice. In the present investigation, we examined the role of endogenous polyamines in transmembrane Ca2+ influx, generation of InsP3 and tyrosine phosphorylation of the p56lck protein in concanavalin A-stimulated splenic T-cells. Cytosolic free calcium concentrations ([Ca2+]i) in concanavalin A-stimulated T-cells of MRL-lpr/lpr and Balb/c mice were 250 +/- 25 and 450 +/- 42 nM respectively. Treatment of MRL-lpr/lpr mice with DFMO increased [Ca2+]i to 360 +/- 30 nM (P < 0.05). InsP3 levels of concanavalin A-stimulated MRL-lpr/lpr splenic T-cells were only 20% higher than those of unstimulated controls, whereas those of Balb/c T-cells were 90% higher. DFMO treatment increased InsP3 levels in concanavalin A-treated MRL-lpr/lpr T-cells to 67%. Western-blot analysis showed a 7-fold higher level of p56lck phosphorylation of MRL-lpr/lpr splenic T-cells than that of Balb/c mice. DFMO treatment reduced tyrosine phosphorylation of p56lck of MRL-lpr/lpr mice significantly (P < 0.001). Two-colour flow-cytometric analysis revealed no significant difference in the CD4+/CD8+ ratio in splenic T-cells of MRL-lpr/lpr mice after DFMO treatment. Polyamine levels in splenocytes were significantly reduced by DFMO treatment. These data show that DFMO treatment could alter signal-transduction pathways of splenic T-cells of MRL-lpr/lpr mice. Increased levels of polyamines in T-cells of untreated lpr mice contribute to defective signal-transduction pathways and the pathogenesis of lupus-like symptoms.

Animals↗
PubMed1997

Transgenic mice overexpressing ornithine and S-adenosylmethionine decarboxylases maintain a physiological polyamine homoeostasis in their tissues.

Recent work has shown that transgenic mice overexpressing human ornithine decarboxylase display no marked changes in the tissue concentrations of spermidine or spermine in spite of a dramatic increase in putrescine levels. In the tissues of transgenic mice carrying the human spermidine synthase gene and in those of hybrid mice overexpressing both ornithine decarboxylase and spermidine synthase, spermidine and spermine levels remain within normal limits. To test whether the amount of the propylamine group donor, decarboxylated S-adenosylmethionine, limits the conversion of putrescine into the higher polyamines, we have produced transgenic mouse lines harbouring the rat S-adenosylmethionine decarboxylase gene in their genome. However, neither these mice nor the hybrid mice overexpressing both ornithine decarboxylase and S-adenosylmethionine decarboxylase displayed significant changes in their spermidine and spermine tissue levels. To study the mechanism by which cells maintain the constancy of the polyamine concentrations, we have determined the metabolic flux of polyamines in transgenic primary fibroblasts using pulse labelling. The results indicate that the polyamine flow is faster in transgenic primary fibroblasts than in non-transgenic fibroblasts and that the intracellular homoeostasis of higher polyamines is maintained at least partly by the acetylation of spermidine and spermine and their secretion into the medium.

Adenosylmethionine Decarboxylase↗
PubMed1997

Interactions of polyamines with ion channels.

Endogenous polyamines, in particular spermine, have been found to cause block and modulation of a number of types of ion channel. Intracellular spermine is responsible for intrinsic gating and rectification of strong inward rectifier K+ channels by directly plugging the ion channel pore. These K+ channels control the resting membrane potential in both excitable and non-excitable cells, and control the excitability threshold in neurons and muscle cells. Intracellular spermine causes inward rectification at some subtypes of Ca2+-permeable glutamate receptors in the central nervous system, again by plugging the receptor channel pore, and spermine can even permeate the ion channel of these receptors. Extracellular spermine has multiple effects at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptor, including stimulation that increases the size of NMDA receptor currents, and voltage-dependent block. A number of polyamine-conjugated arthropod toxins and synthetic polyamine analogues are potent antagonists of glutamate receptors, and represent new tools with which to study these receptors. Interactions of polyamines with other types of cation channels have been reported. This area of research represents a new biology and a new pharmacology of polyamines.

Animals↗
PubMed1990

Polyamines in intestinal growth.

The total cellular mass of the small intestine is well controlled and can adapt, with hypo- or hyperplasia, to a wide variety of stimuli. Luminal nutrients, hormonal factors and pancreatic and biliary secretions have all been implicated in the regulation of intestinal mucosal growth. The polyamines (putrescine, spermidine and spermine) and the key enzyme controlling their synthesis (ornithine decarboxylase. ODC) are critical for many cell growth processes and appear to play important roles in intestinal growth. During intestinal adaptation in response to jejunectomy, lactation. pancreatic-biliary diversion, starvation-refeeding and feeding with kidney bean lectin, intestinal contents of ODC and polyamines are increased, paralleling increases in mucosal proliferative indices and DNA synthesis. With administration of the specific inhibitor of ODC (difluoromethylornithine, DFMO) the increase in ODC and polyamines is inhibited and intestinal growth is suppressed. In addition, the oral administration of exogenous polyamines results in precocious maturation of the neonatal rat intestine. These results suggest that the polyamines are important for intestinal growth.

Adaptation, Physiological↗
PubMed2003

Polyamines as modifiers of genetic risk factors in human intestinal cancers.

Polyamines are downstream mediators of genetic risk factors in human intestinal cancers. The adenomatous polyposis coli (APC) tumour-suppressor gene, which is mutated in essentially all human colon cancers, regulates the expression of several e-box transcription factors. These factors, in turn, regulate the transcription of ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis. The Kirsten ras ( K-ras ) oncogene regulates the expression of several genes, including suppressing the expression of peroxisomal proliferator-activated receptor gamma (PPARgamma). This PPAR, in turn, activates the expression of the spermidine/spermine-N(1)-acetyltransferase (SSAT), the first enzyme in polyamine catabolism. The non-steroidal anti-inflammatory drug (NSAID) sulindac induces the transcription of SSAT via activation of PPARgamma. Inactivation of the APC tumour-suppressor gene, and the activation of K-ras, have a combined effect on increasing tissue polyamine contents due to increased synthesis and decreased catabolism of the polyamines. Pharmacological strategies for suppressing ODC (e.g. the enzyme-activated inhibitor alpha-difluoromethylornithine) and activating SSAT (e.g. NSAIDs) are potent inhibitors of intestinal carcinogenesis in rodent models. Clinical trials combining these classes of agent in humans with risk factors for colon cancer are in progress.

Antineoplastic Agents↗